An inflammatory reaction is a kind of biological defense reaction to tissue damage to be caused by various kinds of invasion and is featured by associated symptoms such as flare, swelling, pyrexia, and pain. Bioactive substances involved in the inflammatory reaction include so-called inflammatory mediators such as histamine, serotonin, and prostaglandin and so-called inflammatory cytokines such as interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factors (TNFs), which are produced by various kinds of cells such as leukocytes (e.g., Shogo Karino, Nobuyuki Miyasaka, and Nagahiro Minato Ed., “Clinical Immunology”, Asakura-Shoten, 1997, p. 73-77).
Interleukin-6 is a polypeptide cytokine consisting of 184 amino acids with a molecular weight of 21 to 28 kDa. Interleukin-6 can be produced from a wide variety of cells such as vascular endothelial cells, T-lymphocytes, B-lymphocytes, monocytes, and macrophages by various kinds of stimulative substances such as lipopolysaccharide, interleukin-1, and TNFs, which can be found in the site of inflammation. As the biological actions of interleukin-6, important actions have been reported, including the acceleration of the synthesis of acute-phase inflammatory protein, induction of the antibody production by B-cells, and the activation of T-lymphocytes. On the other hand, it has been suggested that the abnormality in production of interleukin-6 may deeply relate to various kinds of immunopathy, inflammatory diseases, and lymphoid tumors (e.g., Masahiro Matsumura, Ed., “Dictionary of Molecular Cell Biology”, Tokyo Kagaku Dojin Co., Ltd., 1997, p. 90).
On the other hand, interleukin-6 antibody and interleukin-6 receptor antibody, which inhibit the action of inerleukin-6, have been expected to show effectiveness on various kinds of inflammatory diseases such as autoimmune diseases including rheumatoid arthritis and the like, psoriasis, atrial myxoma, mesangial proliferative nephritis, Castleman syndrome, AIDS, and multiple myeloma (e.g., “Clinical Immunology”, Asakukra-Shoten, 1997, P. 73-77). A therapeutic agent for a disease caused by the production of an interleukin-6 using an antibody against interleukin-6 receptor as an active ingredient (e.g., JP 8-169846 A) and a composition for suppressing interleukin-6 produced by cultured mammalian cells (JP 8-99996 A) have been already disclosed. In addition, it is revealed that, when the anti-inflammatory agent, indomethacin is administered to rats with carrageenan-induced pleurisy, pleuritic inflammation is restrained significantly and interleukin-6 in a peritoneal exudation is inhibited (e.g., “Yakugaku Zasshi”, vol. 120, 2000, p. 455-462).
Regarding the involvement of proteins in milk to interleukin-6, there has been to date disclosed each of the suppressive action of lactoferrin on the urinary level of interleukin-6 in an Escherichia coli urinary tract infection mouse (e.g., “Infection and Immunity”, U.S.A., vol. 68, 2000, p. 5816-5823) and a composition for regulating the ability to produce interleukin containing fermented milk or a processed product thereof as an active ingredient (e.g., JP 5-9124 A).
Lactoperoxidase, one of the milk proteins, is an oxidoreductase not only contained in mammalian milk but also contained in secretions such as saliva, tears, and respiratory mucus (e.g., “American Journal of Respiratory and Critical Care Medicine”, U.S.A., vol. 166, 2002, p. S57-S61), which are industrially purified in large volumes from milk (e.g., JP 5-41981 A).
Various biological functions of lactoperoxidase have been reported, such as antibacterial activity, antiviral activity, antioxidative activity, anticancer activity, and immunoregulating activity (e.g., “Journal of Nutritional Biochemistry”, U.S.A., vol. 11, 2000, p. 94-102; “Life Sciences”, U.S.A., vol. 43, 1988, p. 739-745; “Life Sciences”, U.S.A., vol. 47, 1990, p. 703-709; “Journal of Dairy Research”, U.K., vol. 63, 1996, p. 257-267; “Journal of Dairy Research”, U.K., vol. 64, 1997, p. 281-288; “Veterinary Immunology and Immunopathology”, Holland, vol. 56, 1997, p. 85-96). There are disclosed technologies with respect to the use of lactoperoxidase, peroxide donor, and thiocyanate for the production of therapeutic pharmaceuticals for Helicobacter pylori infection (e.g., JP 2000-509367 A), a preventive and therapeutic agent for the infection of pathogenic bacteria to be added in the mixed feed of farmed aquatic animals (e.g., JP 3103615 B), an age resistor (JP 3103167 B), and a liver-function improving agent (e.g., JP 2001-226289 A), the preventive and therapeutic application of peroxidase (e.g., JP 6-501453 A), and a therapeutic agent for corneal disorder (e.g., JP 2840795 B). Furthermore, the applicant of the present invention has already disclosed a urease-inactivating composition in which peroxidase, thiocyanic acid, and hydrogen peroxide are provided as active ingredients (disclosed in JP 2002-238554 A). However, there has been to date no reports on existing technology at all about the effect of lactoperoxidase on the production of one of inflammatory cytokines, interleukin-6.